The evolution of RNA technology

ANTIBODY OLIGONUCLEOTIDE CONJUGATES (AOCs) DEFINED

AOCs are 3-part molecules consisting of a monoclonal antibody that is conjugated via a linker to one or more oligonucleotides (a small-interfering RNA [siRNA] or phosphonodiamidite morpholino oligomer [PMO]), with the aim of delivering RNA therapy to muscle.^4,11

Depending on the underlying pathophysiological mechanism, siRNA or PMO is selected to be conjugated to the monoclonal antibody, providing a means by which the oligonucleotide can be efficiently delivered to the RNA target.^4,12

The monoclonal antibody portion of AOCs is designed to target the TfR1 receptor, which is highly expressed by muscle cells. After the siRNA or PMO separates from the antibody, the oligonucleotides can bind to their RNA targets and modulate gene expression.^4,12

The monoclonal antibodies have been specifically designed to target the TfR1 receptor with high specificity and affinity, enabling precise delivery of therapies to targeted tissues such as muscle cells.^4,12

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Potential of aocs

Rapid advances in the last few decades have led to multiple approvals of oligonucleotide therapeutics across indications.¹

Effective systemic delivery of oligonucleotide therapeutics requires innovative engineering at multiple levels to potentially achieve safe and effective delivery to target tissues.^1,3

Avidity Biosciences was the first company to demonstrate the successful targeted delivery of RNA to muscle with systemic administration in clinical trials^4,7

The proprietary AOC platform was designed to^4,7:

Combine the specificity of monoclonal antibodies (mAbs) with precise and potent oligonucleotides in one therapeutic conjugate
Enable targeted delivery to affected tissues and address the root cause of disease

Timeline Showing the Progression from Early RNA Therapies to the Introduction of AOCs^8-10

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Avidity’s proprietary aoc platform

PRECISION-ENGINEERED AOCs UNLOCK TARGETED RNA DELIVERY TO TISSUES⁴

Avidity's AOCs are purposefully engineered to reach previously unreachable cell types with potentially fewer off-target effects.

Each component of the AOC platform is engineered with the intent to increase precision, durability, potency, and safety—with the ultimate goal of providing customized treatments for a range of genetic neuromuscular disorders.^4,11

See how avidity’s aoc comes together

Monoclonal antibody^4,11

Designed for tissue-specific delivery
- The mAB is designed to target the alpha TfR1 receptor and deliver siRNA or PMO into the cell
  - Precision: High specificity for alpha TfR1 receptors
  - Safety: Designed to minimize immunogenicity and reduce toxicity
  - Durability: Long half-life

LINKER^4,11

Designed to maintain structural integrity of the AOC
- The linker attaches mAb to oligonucleotide and is designed to maximize the stability and durability of the conjugate
  - Stability: Enhanced for stability in circulation

Oligonucleotide (siRNA or PMO)^4,11

Designed to modify target RNA to address the root cause of disease
- The oligonucleotide targets mRNA sequence to modify the gene expression of relevant gene; siRNAs or PMOs can be used based on the specific mechanism of the disease
  - Potency: Optimized drug-antibody ratio allows for minimized overall dose
  - Precision: Designed to engage their RNA targets with high binding affinity and specificity
  - Safety: Designed to reduce off-target effects
  - Durability: Designed to withstand metabolic breakdown with sustained activity

Advancing Research & Development of the AOC Platform

Avidity is now expanding research and development of RNA therapeutics beyond neuromuscular diseases into new therapeutic areas, such as cardiology and immunology.

Avidity is committed to redefining what’s possible for people living with rare neuromuscular diseases—such as Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and myotonic dystrophy type 1 (DM1)—through investigation and development of RNA-targeted therapeutics powered by its proprietary AOC platform.

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AOC=antibody oligonucleotide conjugate; ED50=effective dose in 50% of the population; mAb=monoclonal antibody; PMO=phosphorodiamidate morpholino oligomer; siRNA=short interfering RNA; DMD=Duchenne muscular dystrophy; FSHD=facioscapulohumeral muscular dystrophy; DM1= myotonic dystrophy type 1.

References:

Lauffer MC, van Roon-Mom W, Aartsma-Rus A; N = 1 Collaborative. Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun Med (Lond). 2024;4(1):6. Published 2024 Jan 5. doi:10.1038/s43856-023-00419-1
Kulkarni JA, Witzigmann D, Thomson SB, et al. The current landscape of nucleic acid therapeutics [published correction appears in Nat Nanotechnol. 2021 Jul;16(7):841. doi: 10.1038/s41565-021-00937-w.]. Nat Nanotechnol. 2021;16(6):630-643. doi:10.1038/s41565-021-00898-0
Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673-694. doi:10.1038/s41573-020-0075-7
Malecova B, Burke RS, Cochran M, et al. Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs). Nucleic Acids Res. 2023;51(12):5901-5910. doi:10.1093/nar/gkad415
Moumné L, Marie AC, Crouvezier N. Oligonucleotide Therapeutics: From Discovery and Development to Patentability. Pharmaceutics. 2022;14(2):260. Published 2022 Jan 22. doi:10.3390/pharmaceutics14020260
Hammond SM, Aartsma-Rus A, Alves S, et al. Delivery of oligonucleotide-based therapeutics: challenges and opportunities. EMBO Mol Med. 2021;13(4):e13243. doi:10.15252/emmm.202013243
PR Newswire 2022
Kim YK. RNA therapy: rich history, various applications and unlimited future prospects. Exp Mol Med. 2022;54(4):455-465. doi:10.1038/s12276-022-00757-5
Zhu 2022 Zhu Y, Zhu L, Wang X, Jin H. RNA-based therapeutics: an overview and prospectus. Cell Death Dis. 2022;13(7):644. Published 2022 Jul 23. doi:10.1038/s41419-022-05075-2
Tang Q, Khvorova A. RNAi-based drug design: considerations and future directions. Nat Rev Drug Discov. 2024;23(5):341-364. doi:10.1038/s41573-024-00912-9\
Cochran M, Arias D, Burke R, et al. Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-siRNA Conjugates for Drug Development. J Med Chem. 2024;67(17):14852-14867. doi:10.1021/acs.jmedchem.4c00802
Li Y, Cheng JX, Yang HH, et al. Transferrin receptor 1 plays an important role in muscle development and denervation-induced muscular atrophy. Neural Regen Res. 2021;16(7):1308-1316. doi:10.4103/1673-5374.301024
Johnson N, Thronton C, Day J, et al. Phase 3, Randomized, Global Study Assessing Efficacy and Safety of Del-desiran for the Treatment of Myotonic Dystrophy Type 1: HARBOR Trial Design. Poster presented at 29th Annual Congress of the World Muscle Society, Prague, Czechia, October 2024.
Stahl M, Zhu Y, Goel V, et al. AOC 1044 as a Novel Therapeutic Approach for DMD Patients Amenable to Exon 44 Skipping: EXPLORE44TM Phase 1/2 Healthy Volunteer Data. Poster presented at MDA Clinical & Scientific Conference. Orlando, FL, March 2024.